Indole, azaindole and related heterocyclic pyrrolidine derivatives

ABSTRACT

This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with amido piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/356,977 filed Feb. 14, 2002.

FIELD OF THE INVENTION

This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and method of use. Inparticular, the invention is concerned with new heterocyclicamidopiperazine derivatives that possess unique antiviral activity. Moreparticularly, the present invention relates to compounds useful for thetreatment of HIV and AIDS.

BACKGROUND ART

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 33.6 million people infected worldwide. Thenumber of cases of HIV and AIDS (acquired immunodeficiency syndrome) hasrisen rapidly. In 1999, 5.6 million new infections were reported, and2.6 million people died from AIDS. Currently available drugs for thetreatment of HIV include six nucleoside reverse transcriptase (RT)inhibitors (zidovudine, didanosine, stavudine, lamivudine, zalcitabineand abacavir), three non-nucleoside reverse transcriptase inhibitors(nevirapine, delavirdine and efavirenz), and six peptidomimetic proteaseinhibitors (saquinavir, indinavir, ritonavir, nelfinavir, amprenavir andlopinavir). Each of these drugs can only transiently restrain viralreplication if used alone. However, when used in combination, thesedrugs have a profound effect on viremia and disease progression. Infact, significant reductions in death rates among AIDS patients havebeen recently documented as a consequence of the widespread applicationof combination therapy. However, despite these impressive results, 30 to50% of patients ultimately fail combination drug therapies. Insufficientdrug potency, non-compliance, restricted tissue penetration anddrug-specific limitations within certain cell types (e.g. mostnucleoside analogs cannot be phosphorylated in resting cells) mayaccount for the incomplete suppression of sensitive viruses.Furthermore, the high replication rate and rapid turnover of HIV-1combined with the frequent incorporation of mutations, leads to theappearance of drug-resistant variants and treatment failures whensub-optimal drug concentrations are present (Larder and Kemp; Gulick;Kuritzkes; Morris-Jones et al; Schinazi et al; Vacca and Condra;Flexner; Berkhout and Ren et al; (Ref. 6-14)). Therefore, novel anti-HIVagents exhibiting distinct resistance patterns, and favorablepharmacokinetic as well as safety profiles are needed to provide moretreatment options.

Currently marketed HIV-1 drugs are dominated by either nucleosidereverse transcriptase inhibitors or peptidomimetic protease inhibitors.Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recentlygained an increasingly important role in the therapy of HIV infections(Pedersen & Pedersen, Ref 15). At least 30 different classes of NNRTIhave been described in the literature (De Clercq, Ref. 16) and severalNNRTIs have been evaluated in clinical trials. Dipyridodiazepinone(nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl)piperazinederivatives (delavirdine) have been approved for clinical use. However,the major drawback to the development and application of NNRTIs is thepropensity for rapid emergence of drug resistant strains, both in tissuecell culture and in treated individuals, particularly those subject tomonotherapy. As a consequence, there is considerable interest in theidentification of NNRTIs less prone to the development of resistance(Pedersen & Pedersen, Ref 15). A recent overview of non-nucleosidereverse transcriptase inhibitors: perspectives on novel therapeuticcompounds and strategies for the treatment of HIV infection has appeared(Buckheit, reference 99). A review covering both NRTI and NNRTIs hasappeared (De clercq, reference 100). An overview of the current state ofthe HIV drugs has been published (De clercq, reference 101)

Several indole derivatives including indole-3-sulfones, piperazinoindoles, pyrazino indoles, and 5H-indolo[3,2-b][1,5]benzothiazepinederivatives have been reported as HIV-1 reverse transciptase inhibitors(Greenlee et al, Ref. 1; Williams et al, Ref. 2; Romero et al, Ref. 3;Font et al, Ref. 17; Romero et al, Ref. 18; Young et al, Ref. 19; Geninet al, Ref. 20; Silvestri et al, Ref. 21). Indole 2-carboxamides havealso been described as inhibitors of cell adhesion and HIV infection(Boschelli et al, U.S. Pat. No. 5,424,329, Ref. 4). 3-substituted indolenatural products (Semicochliodinol A and B, didemethylasterriquinone andisocochliodinol) were disclosed as inhibitors of HIV-1 protease(Fredenhagen et al, Ref. 22).

Structurally related aza-indole amide derivatives have been disclosedpreviously (Kato et al, Ref. 23; Levacher et al, Ref. 24; Dompe Spa,WO-09504742, Ref. 5(a); SmithKline Beecham PLC, WO-09611929, Ref. 5(b);Schering Corp., U.S. Pat. No. 5,023,265, Ref. 5(c)). However, thesestructures differ from those claimed herein in that they are aza-indolemono-amide rather than unsymmetrical aza-indole piperazine diamidederivatives, and there is no mention of the use of these compounds fortreating viral infections, particularly HIV. Indole and azaindolepiperazine containing derivatives have been disclosed in three differentPCT patent applications (Reference 93-95) None of these applicationsdiscloses pyrrolidine compounds such as described in this invention.

Nothing in these references can be construed to disclose or suggest thenovel compounds of this invention and their use to inhibit HIVinfection.

REFERENCES CITED

Patent Documents

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SUMMARY OF THE INVENTION

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to a virus such as HIV. The compounds of Formula I, whichinclude nontoxic pharmaceutically acceptable salts and/or hydratesthereof, have the formula and meaning as described below. Eachembodiment of a particular aspect of the invention depends from thepreceding embodiment unless otherwise stated.

SUMMARY DESCRIPTION OF THE INVENTION

The present invention comprises compounds of Formula I, orpharmaceutically acceptable salts thereof, which are effective antiviralagents, particularly as inhibitors of HIV.

A first embodiment of a first aspect of the invention are compounds ofFormula I, including pharmaceutically acceptable salts thereof,

wherein:

-   Z is

-   Q is selected from the group consisting of:

-   R¹, R², R³, R⁴, and R⁵, are independently selected from the group    consisting of hydrogen, halogen, cyano, nitro, COOR⁸, XR⁵⁷, and B;-   m is 1 or 2;-   R⁷ is (CH₂)_(n)R⁴⁴ wherein n is 0-6;-   R⁶ is O or does not exist;    -   — represents a carbon-carbon bond or does not exist;-   A is selected from the group consisting of C₁₋₆alkoxy, phenyl and D;    wherein D is selected from the group consisting of pyridinyl,    pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl,    imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,    quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl,    benzoimidazolyl and benzothiazolyl; wherein said phenyl and D are    independently optionally substituted with one or two of the same or    different amino, halogen or trifluoromethyl;-   —W— is

-   B is selected from the group consisting of (C₁₋₆)alkyl,    (C₃₋₆)cycloalkyl, C(O)NR⁴⁰R⁴¹, phenyl and heteroaryl; wherein said    (C₁₋₆)alkyl, phenyl and heteroaryl are independently optionally    substituted with one to three same or different halogens or from one    to three same or different substituents selected from F;-   F is selected from the group consisting of (C₁₋₆)alkyl, phenyl,    hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl,    —NR⁴²R⁴³, COOR⁵⁴ and —CONR⁴²; wherein said (C₁₋₆)alkyl is optionally    substituted with one to three same or different halogen;-   R⁸ is selected from the group consisting of hydrogen and    (C₁₋₆)alkyl;-   R⁹ is selected from the group consisting of hydrogen and methyl;-   X is selected from the group consisting of NR⁹, O and S;-   R⁴⁰ and R⁴¹ are independently selected from the group consisting of    hydrogen, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, phenyl and heteroaryl; wherein    said phenyl and heteroaryl are independently optionally substituted    with one to three same or different halogen, methyl, or CF₃ groups;-   R⁴² and R⁴³ are independently selected from the group consisting of    hydrogen and (C₁₋₆)alkyl;-   R⁴⁴ is selected from the group consisting of H, (C₁₋₆)alkyl,    CO(C₁₋₆)alkyl, C(O)— phenyl and —CONR_(a)R_(b);-   R_(a) and R_(b) are each independently H, (C₁₋₆)alkyl or phenyl;-   R⁵⁴ is selected from the group consisting of hydrogen and    (C₁₋₆)alkyl;-   R⁵⁷ is (C₁₋₆)alkyl; and-   heteroaryl is selected from the group consisting of pyridinyl,    pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl,    thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl,    imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,    1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,    tetrazolyl, tetrazinyl, triazinyl and triazolyl.

A more preferred embodiment of a first aspect of the invention arecompounds of Formula I, including pharmaceutically acceptable saltsthereof,

wherein:

-   Z is

A is selected from the group consisting of phenyl and D; wherein D isselected from the group consisting of pyridinyl, furanyl and thienyl;wherein phenyl and D are independently optionally substituted with oneor two of the same or different amino or halogen;

W is selected from the group consisting of

-   R¹ is hydrogen; and-   Q is a member selected from groups (A) and (B) consisting of

-   -   provided R² and R³ are each independently hydrogen, methoxy or        halogen; and R⁴ and R⁵ are selected from the group consisting of        hydrogen, halogen, cyano, COOR⁸, C(O)NHCH₃, C(O)NHheteroaryl,        and heteroaryl; and

-   -   provided R² is hydrogen, methoxy or halogen;    -   R³ and R⁴ are selected from the group consisting of hydrogen,        halogen, methoxy, cyano, COOR⁸, C(O)NHCH₃, C(O)NHheteroaryl and        heteroaryl; and R⁶ does not exist;    -   and — represents a carbon-carbon bond in (A) and (B).

Another embodiment of the present invention is a method for treatingmammals infected with a virus, wherein said virus is HIV, comprisingadministering to said mammal an antiviral effective amount of a compoundof Formula I, and one or more pharmaceutically acceptable carriers,excipients or diluents; optionally the compound of Formula I can beadministered in combination with an antiviral effective amount of anAIDS treatment agent selected from the group consisting of: (a) an AIDSantiviral agent; (b) an anti-infective agent; (c) an immunomodulator;and (d) HIV entry inhibitors.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising an antiviral effective amount of a compound ofFormula I and one or more pharmaceutically acceptable carriers,excipients, diluents and optionally in combination with an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) HIV entry inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

Since the compounds of the present invention, may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present invention includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof

Definitions

The term “C₁₋₆alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. It should be noted that the termheteroaryl is intended to encompass an N-oxide of the parent heteroarylif such an N-oxide is chemically feasible as is known in the art.Examples, without limitation, of heteroaryl groups are furyl, thienyl,benzothienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl,thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl,isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl,pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl,benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, pyrazinyl, diazinyl,pyrazine, triazinyltriazine, tetrazinyl, and tetrazolyl. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexadiene, cycloheptane, cycloheptatriene and adamantane. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroarylloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalo-methanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) with R^(x)and R^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbondouble bond.

An “alkynyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbontriple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroaliacyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O— group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z and R^(X) as defined herein.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ as definedherein and, in addition, as a bond only; i.e., —S(O)—.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ as defined hereinand, in addition as a bond only; i.e., —S(O)₂—.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(X)R^(Y), with R^(X) andR^(Y) as defined herein.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(X)— group with R_(x) asdefined herein.

A “O-carbamyl” group refers to a —OC(═O)NR^(x)R^(y) as defined herein.

A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, with R^(x) andR^(y) as defined herein.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group with R^(x)and R^(y) as defined herein.

A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— group with R^(x)and R^(y) as defined herein.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group with R^(x) andR^(y) as defined herein.

A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, with R^(x)and R^(y) as defined herein.

A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x) andR^(y) as defined herein.

An “ureido” group refers to a —NR^(x)C(═O)NR^(y)R^(y2) group with R^(x)and R^(y) as defined herein and R^(y2) defined the same as R^(x) andR^(y).

A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y) and R^(y2) as defined herein.

A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(Y) as defined herein.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ as defined herein.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) as definedherein.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group with R^(x),R^(y) and R^(y2) as defined herein.

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present invention are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Physiologically acceptable salts and prodrugs of compounds disclosedherein are within the scope of this invention. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g. hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

In the method of the present invention, the term “antiviral effectiveamount” means the total amount of each active component of the methodthat is sufficient to show a meaningful patient benefit, i.e., healingof acute conditions characterized by inhibition of the HIV infection.When applied to an individual active ingredient, administered alone, theterm refers to that ingredient alone. When applied to a combination, theterm refers to combined amounts of the active ingredients that result inthe therapeutic effect, whether administered in combination, serially orsimultaneously. The terms “treat, treating, treatment” as used hereinand in the claims means preventing or ameliorating diseases associatedwith HIV infection.

The present invention is also directed to combinations of the compoundswith one or more agents useful in the treatment of AIDS. For example,the compounds of this invention may be effectively administered, whetherat periods of pre-exposure and/or post-exposure, in combination witheffective amounts of the AIDS antivirals, immunomodulators,antiinfectives, or vaccines, such as those in the following table.

Drug Name Manufacturer Indication ANTIVIRALS 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse tran- scriptase (RT)inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, AIDS, GW 1592 ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC,in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA)HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIVin combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha (Rockville, MD) aberrantInterferon AR 177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer AIDS-associated Institute diseases BMS-232623 Bristol-MyersHIV infection, (CGP-73547) Squibb/Novartis AIDS, ARC (proteaseinhibitor) BMS-234475 Bristol-Myers HIV infection, (CGP-61755)Squibb/Novartis AIDS, ARC (protease inhibitor) CI-1012 Warner-LambertHIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes,papillomavirus Curdlan sulfate AJI Pharma USA HIV infectionCytomegalovirus MedImmune CMV retinitis Immune globin Cytovene SyntexSight threatening Ganciclovir CMV peripheral CMV retinitis DelaviridinePharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran SulfateUeno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan)asymptomatic ddC Hoffman-La Roche HIV infection, AIDS, DideoxycytidineARC ddI Bristol-Myers HIV infection, AIDS, Dideoxyinosine Squibb ARC;combination with AZT/d4T DMP-450 AVID HIV infection, AIDS, (Camden, NJ)ARC (protease inhibitor) Efavirenz DuPont Merck HIV infection, (DMP 266)AIDS, ARC (−)6-Chloro-4-(S)- (non-nucleoside RT cyclopropylethynyl-inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one,STOCRINE EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FamciclovirSmith Kline herpes zoster, herpes simplex FTC Emory University HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 HoechstMarion HIV infection, Roussel AIDS, ARC (non- nucleoside reversetranscriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARCRecombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta(Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon ARC, AIDSSciences Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISIS CMVretinitis Pharmaceuticals KNI-272 Nat'l Cancer HIV-assoc. diseasesInstitute Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC(reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-MyersCMV infection Squibb Nelfinavir Agouron HIV infection, PharmaceuticalsAIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection,AIDS, Ingleheim ARC (RT inhibitor) Novapren Novaferon Labs, HIVinhibitor Inc. (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide(Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIVPhosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (proteaseinhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, AIDS, Tech (Houston, TX) ARC Ritonavir Abbott HIV infection,AIDS, ARC (protease inhibitor) Saquinavir Hoffmann-LaRoche HIVinfection, AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-MyersHIV infection, AIDS, Didehydrodeoxy- Squibb ARC thymidine ValaciclovirGlaxo Wellcome Genital HSV &CMV infections Virazole Viratek/ICNasymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIVinfection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIVinfection, AIDS, ARC, Kaposi's sarcoma, in combination with othertherapies IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS BropiriminePharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, AIDS, ARC Inc.(Irving, TX) CL246, 738 American Cyanamid AIDS, Kaposi's Lederle Labssarcoma EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells Gamma InterferonGenentech ARC, in combination w/TNF (tumor necrosis factor) GranulocyteGenetics Institute AIDS Macrophage Colony Sandoz Stimulating FactorGranulocyte Hoechst-Roussel AIDS Macrophage Colony Immunex StimulatingFactor Granulocyte Schering-Plough AIDS, combination Macrophage Colonyw/AZT Stimulating Factor HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in Interleukin-2 combination w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Interleukin-2 Chiron AIDS, increase in (aldeslukin) CD4 cellcounts Immune Globulin Cutter Biological Pediatric AIDS, in Intravenous(human) (Berkeley, CA) combination w/AZT IMREG-1 Imreg AIDS, Kaposi's(New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (NewOrleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute AIDS,ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferonw/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin(Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcomaMuramyl-Tripeptide Granulocyte Colony Amgen AIDS, in Stimulating Factorcombination w/AZT Remune Immune Response Immunotherapeutic Corp. rCD4Recombinant Genentech AIDS, ARC Soluble Human CD4 rCD4-IgG hybrids AIDS,ARC Recombinant Biogen AIDS, ARC Soluble Human CD4 Interferon Hoffman-LaRoche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combination w/AZTSK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma InterferonANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP PrimaquineFluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille SquibbCorp. Prevention of Nystatin Pastille oral candidiasis OrnidylEflornithine Merrell Dow PCP Pentamidine LyphoMed PCP treatmentIsethionate (IM &IV) (Rosemont, IL) Trimethoprim AntibacterialTrimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCPtreatment Pentamidine Isethionate Fisons Corporation PCP prophylaxis forInhalation Spiramycin Rhone-Poulenc Cryptosporidial diarrheaIntraconazole- Janssen-Pharm. Histoplasmosis; R51211 cryptococcalmeningitis Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, SequusKaposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemiaassoc. Erythropoietin with AZT therapy Recombinant Human SeronoAIDS-related Growth Hormone wasting, cachexia Megestrol AcetateBristol-Myers Treatment of Squibb anorexia assoc. W/AIDS TestosteroneAlza, Smith Kline AIDS-related wasting Total Enteral Norwich EatonDiarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS

Additionally, the compounds of the invention herein may be used incombination with another class of agents for treating AIDS which arecalled HIV entry inhibitors. Examples of such HIV entry inhibitors arediscussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol.9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5,May 2000, pp. 183-194.

It will be understood that the scope of combinations of the compounds ofthis invention with AIDS antivirals, immunomodulators, anti-infectives,HIV entry inhibitors or vaccines is not limited to the list in the aboveTable, but includes in principle any combination with any pharmaceuticalcomposition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments ofwith a compound of the present invention and an inhibitor of HIVprotease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.An optional fourth component in the combination is a nucleosideinhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. Apreferred inhibitor of HIV protease is indinavir, which is the sulfatesalt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations include thosewith the following (1) indinavir with efavirenz, and, optionally, AZTand/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/orddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Abbreviations

The following abbreviations, most of which are conventionalabbreviations well known to those skilled in the art, are usedthroughout the description of the invention and the examples. Some ofthe abbreviations used are as follows:

-   h=hour(s)-   rt=room temperature-   mol=mole(s)-   mmol=millimole(s)-   g=gram(s)-   mg=milligram(s)-   mL=milliliter(s)-   TFA=Trifluoroacetic Acid-   DCE=1,2-Dichloroethane-   CH₂Cl₂=Dichloromethane-   TPAP=tetrapropylammonium perruthenate-   THF=Tetrahydrofuran-   DEPBT=3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one-   DMAP=4-dimethylaminopyridine-   P-EDC=Polymer supported    1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   DMF=N,N-dimethylformamide-   Hunig's Base=N,N-Diisopropylethylamine-   mCPBA=meta-Chloroperbenzoic Acid-   azaindole=1H-Pyrrolo-pyridine-   4-azaindole=1H-pyrrolo[3,2-b]pyridine-   5-azaindole=1H-Pyrrolo[3,2-c]pyridine-   6-azaindole=1H-pyrrolo[2,3-c]pyridine-   7-azaindole=1H-Pyrrolo[2,3-b]pyridine-   PMB=4-Methoxybenzyl-   DDQ=2,3-Dichloro-5,6-dicyano-1,4-benzoquinone-   OTf=Trifluoromethanesulfonoxy-   NMM=4-Methylmorpholine-   PIP-COPh=1-Benzoylpiperazine-   NaHMDS=Sodium hexamethyldisilazide-   EDAC=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide-   TMS=Trimethylsilyl-   DCM=Dichloromethane-   DCE=Dichloroethane-   MeOH=Methanol-   THF=Tetrahrdrofuran-   EtOAc=Ethyl Acetate-   LDA=Lithium diisopropylamide-   TMP-Li=2,2,6,6-tetramethylpiperidinyl lithium-   DME=Dimethoxyethane-   DIBALH=Diisobutylaluminum hydride-   HOBT=1-hydroxybenzotriazole-   CBZ=Benzyloxycarbonyl-   PCC=Pyridinium chlorochromate    Chemistry

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof.

The synthesis procedures and anti-HIV-1 activities of indoleoxoaceticpyrrolidine containing analogs are below. Procedures for making Z aredescribed herein or in many cases references of Blair, Wang, Wallace,references 93-95 respectively.

Additional general procedures to construct substituted azaindole Q and Zof Formula I and intermediates useful for their synthesis are describedin the following Schemes 1-16.

Step A in Scheme 1 depicts the synthesis of an aza indole intermediate,2, via the well known Bartoli reaction in which vinyl magnesium bromidereacts with an aryl or heteroaryl nitro group, such as in 1, to form afive-membered nitrogen containing ring as shown. Some references for theabove transformation include: Bartoli et al. a) Tetrahedron Lett. 1989,30, 2129. b) J. Chem. Soc. Perkin Trans. 1 1991, 2757. c) J. Chem. Soc.Perkin Trans. II 1991, 657. d) Synthesis (1999), 1594. In the preferredprocedure, a solution of vinyl Magnesium bromide in THF (typically 1.0Mbut from 0.25 to 3.0M) is added dropwise to a solution of the nitropyridine in THF at −78° under an inert atmosphere of either nitrogen orArgon. After addition is completed, the reaction temperature is allowedto warm to −20° and then is stirred for approximately 12 h beforequenching with 20% aq ammonium chloride solution. The reaction isextracted with ethyl acetate and then worked up in a typical mannerusing a drying agent such as anhydrous magnesium sulfate or sodiumsulfate. Products are generally purified using chromatography overSilica gel. Best results are generally achieved using freshly preparedvinyl Magnesium bromide. In some cases, vinyl Magnesium chloride may besubstituted for vinyl Magnesium bromide.

Substituted azaindoles may be prepared by methods described in theliterature or may be available from commercial sources. Thus there aremany methods for carrying out step A in the literature and the specificexamples are too numerous to even list. A review on the synthesis of7-azaindoles has been published (Merour et. al. reference 102).Alternative syntheses of aza indoles and general methods for carryingout step A include, but are not limited to, those described in thefollowing references (a-k below): a) Prokopov, A. A.; Yakhontov, L. N.Khim.-Farm. Zh. 1994, 28(7), 30-51; b) Lablache-Combier, A.Heteroaromatics. Photoinduced Electron Transfer 1988, Pt. C, 134-312; c)Saify, Zafar Said. Pak. J. Pharmacol. 1986, 2(2), 43-6; d) Bisagni, E.Jerusalem Symp. Quantum Chem. Biochem. 1972, 4, 439-45; e) Yakhontov, L.N. Usp. Khim. 1968, 37(7), 1258-87; f) Willette, R. E. Advan.Heterocycl. Chem. 1968, 9, 27-105; g) Mahadevan, I.; Rasmussen, M.Tetrahedron 1993, 49(33), 7337-52; h) Mahadevan, I.; Rasmussen, M. J.Heterocycl. Chem. 1992, 29(2), 359-67; i) Spivey, A. C.; Fekner, T.;Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443; j) Spivey,A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39(48), 8919-8922;k) Advances in Heterocyclic Chemistry (Academic press) 1991, Vol. 52, pg235-236 and references therein.

Step B. Intermediate 3 can be prepared by reaction of aza-indole,intermediate 2, with an excess of ClCOCOOMe in the presence of AlCl₃(aluminum chloride) (Sycheva et al, Ref. 26, Sycheva, T. V.; Rubtsov, N.M.; Sheinker, Yu. N.; Yakhontov, L. N. Some reactions of5-cyano-6-chloro-7-azaindoles and lactam-lactim tautomerism in5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl. Soedin., 1987,100-106). Typically an inert solvent such as CH₂Cl₂ is used but otherssuch as THF, Et₂O, DCE, dioxane, benzene, or toluene may findapplicability either alone or in mixtures. Other oxalate esters such asethyl or benzyl mono esters of oxalic acid could also suffice for eithermethod shown above. More lipophilic esters ease isolation during aqueousextractions. Phenolic or substituted phenolic (such aspentafluorophenol) esters enable direct coupling of the HW(C═O)A group,such as a piperazine, in Step D without activation. Lewis acidcatalysts, such as tin tetrachloride, titanium IV chloride, and aluminumchloride are employed in Step B with aluminum chloride being mostpreferred. Alternatively, the azaindole is treated with a Grignardreagent such as MeMgI (methyl magnesium iodide), methyl magnesiumbromide or ethyl magnesium bromide and a zinc halide, such as ZnCl₂(zinc chloride) or zinc bromide, followed by the addition of an oxalylchloride mono ester, such as ClCOCOOMe (methyl chlorooxoacetate) oranother ester as above, to afford the aza-indole glyoxyl ester (Shadrinaet al, Ref. 25). Oxalic acid esters such as methyl oxalate, ethyloxalate or as above are used. Aprotic solvents such as CH₂Cl₂, Et₂O,benzene, toluene, DCE, or the like may be used alone or in combinationfor this sequence. In addition to the oxalyl chloride mono esters,oxalyl chloride itself may be reacted with the azaindole and thenfurther reacted with an appropriate amine, such as a piperazinederivative (See Scheme 52, for example).

Step C. Hydrolysis of the methyl ester, (intermediate 3, Scheme 1)affords a potassium salt of intermediate 4, which is coupled withmono-benzoylated piperazine derivatives as shown in Step D of Scheme 1.Some typical conditions employ methanolic or ethanolic sodium hydroxidefollowed by careful acidification with aqueous hydrochloric acid ofvarying molarity but 1M HCl is preferred. The acidification is notutilized in many cases as described above for the preferred conditions.Lithium hydroxide or potassium hydroxide could also be employed andvarying amounts of water could be added to the alcohols. Propanols orbutanols could also be used as solvents. Elevated temperatures up to theboiling points of the solvents may be utilized if ambient temperaturesdo not suffice. Alternatively, the hydrolysis may be carried out in anon polar solvent such as CH₂Cl₂ or THF in the presence of Triton B.Temperatures of −78° C. to the boiling point of the solvent may beemployed but −10° C. is preferred. Other conditions for ester hydrolysisare listed in reference 41 and both this reference and many of theconditions for ester hydrolysis are well known to chemists of averageskill in the art.

Alternative Procedures for Step B and C:

Imidazolium Chloroaluminate:

We found that ionic liquid 1-alkyl-3-alkylimidazolium chloroaluminate isgenerally useful in promoting the Friedel-Crafts type acylation ofindoles and azaindoles. The ionic liquid is generated by mixing1-alkyl-3-alkylimidazolium chloride with aluminium chloride at roomtemperature with vigorous stirring. 1:2 or 1:3 molar ratio of1-alkyl-3-alkylimidazolium chloride to aluminium chloride is preferred.One particular useful imidazolium chloroaluminate for the acylation ofazaindole with methyl or ethyl chlorooxoacetate is the1-ethyl-3-methylimidazolium chloroaluminate. The reaction is typicallyperformed at ambient temperature and the azaindoleglyoxyl ester can beisolated. More conveniently, we found that the glyoxyl ester can behydrolyzed in situ at ambient temperature on prolonged reaction time(typically overnight) to give the corresponding glyoxyl acid for amideformation (Scheme 2).

A representative experimental procedure is as follows:1-ethyl-3-methylimidazolium chloride (2 equiv.; purchased from TCI;weighted under a stream of nitrogen) was stirred in an oven-dried roundbottom flask at r.t. under a nitrogen atmosphere, and added aluminiumchloride (6 equiv.; anhydrous powder packaged under argon in ampulespurchased from Aldrich preferred; weighted under a stream of nitrogen).The mixture was vigorously stirred to form a liquid, which was thenadded azaindole (1 equiv.) and stirred until a homogenous mixtureresulted. The reaction mixture was added dropwise ethyl or methylchlorooxoacetate (2 equiv.) and then stirred at r.t. for 16 h. Afterwhich time, the mixture was cooled in an ice-water bath and the reactionquenched by carefully adding excess water. The precipitates werefiltered, washed with water and dried under high vacuum to give theazaindoleglyoxyl acid. For some examples, 3 equivalents of1-ethyl-3-methylimidazolium chloride and chlorooxoacetate may berequired.

Related references: (1) Welton, T. Chem. Rev. 1999, 99, 2071; (2)Surette, J. K. D.; Green, L.; Singer, R. D. Chem. Commun. 1996, 2753;(3) Saleh, R. Y. WO 0015594.

Step D. The acid intermediate, 4, from step C of Scheme 1 is coupledwith an amine A(C═O)WH preferably in the presence of DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) andN,N-diisopropylethylamine, commonly known as Hunig's base, to provideazaindole piperazine diamides. DEPBT was prepared according to theprocedure of Ref. 28, Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.;Goodman, M. Organic Lett., 1999, 1, 91-93. Typically an inert solventsuch as DMF or THF is used but other aprotic solvents could be used. Thegroup W as referred to herein is described below.

The amide bond construction reaction could be carried out using thepreferred conditions described above, the EDC conditions describedbelow, other coupling conditions described in this application, oralternatively by applying the conditions or coupling reagents for amidebond construction described later in this application for constructionof substituents R₁-R₄. Some specific nonlimiting examples are given inthis application.

It should be noted that in many cases reactions are depicted for onlyone position of an intermediate, such as the R⁵ position, for example.It is to be understood that such reactions could be used at otherpositions, such as R²-R⁴, of the various intermediates. Reactionconditions and methods given in the specific examples are broadlyapplicable to compounds with other substitution and othertransformations in this application. Schemes 1 and 2 describe generalreaction schemes for taking appropriately substituted Q (indoles andazaindoles) and converting them to compounds of Formula I. While theseschemes are very general, other permutations such as carrying aprecursor or precursors to substituents R² through R⁵ through thereaction scheme and then converting it to a compound of Formula I in thelast step are also contemplated methods of this invention. Nonlimitingexamples of such strategies follow in subsequent schemes.

The amide coupling with amine H—W—C(O)A is shown in Scheme 3, step a3.The group W as referred to herein is either

One preferred method for carrying out this reaction is the use of thepeptide coupling reagent3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) and anamine H—W—C(O)A in DMF solvent containing a tertiary amine such asN,N-diisopropylethylamine. Commonly used amide bond coupling conditions,e.g. EDC with HOBT or DMAP, are also employed in some examples. Typicalstoichiometries are given in the specific examples but these ratios maybe modified.

The amide bond construction reactions depicted in step a3 or step a5 ofSchemes 3 and 4 respectively could be carried out using the specializedconditions described herein or alternatively by applying the conditionsor coupling reagents for amide bond construction described in Wallace,reference 95. Some specific nonlimiting examples are given in thisapplication.

Additional procedures for synthesizing, modifying and attaching groups:WC(O)-A are contained in references 93-95 or described below except thatthe piperazine intermediates are replaced by the pyrrolidines describedherein.

Scheme 4a provides a more specific example of the transformationspreviously described in Scheme 1. Intermediates 6-10 are prepared by themethodologies as described for intermediates 1a-5a in Scheme 1. Scheme 5is another embodiment of the transformations described in Schemes 1 and4a. Conversion of the phenol to the chloride (Step S, Scheme 5) may beaccomplished according to the procedures described in Reimann, E.;Wichmann, P.; Hoefner, G.; Sci. Pharm. 1996, 64(3), 637-646; andKatritzky, A. R.; Rachwal, S.; Smith, T. P.; Steel, P. J.; J.Heterocycl. Chem. 1995, 32(3), 979-984. Step T of Scheme 5 can becarried out as described for Step A of Scheme 3. The bromo intermediatecan then be converted into alkoxy, chloro, or fluoro intermediates asshown in Step U of Scheme 5. Scheme 2A describes the preferred methodfor preparing intermediate 6c or other closely related compoundscontaining a 4 methoxy group in the 6-azaindole system. When step U isthe conversion of the bromide into alkoxy derivatives, the conversionmay be carried out by reacting the bromide with an excess of sodiummethoxide in methanol with cuprous salts, such as copper I bromide,copper I iodide, and copper I cyanide. The temperature may be carriedout at temperatures of between ambient and 175° but most likely will bearound 115° C. or 100° C. The reaction may be run in a pressure vesselor sealed tube to prevent escape of volatiles such as methanol. Thepreferred conditions utilize 3 eq of sodium methoxide in methanol, CuBras the reaction catalyst (0.2 to 3 equivalents with the preferred being1 eq or less), and a reaction temperature of 115° C. The reaction iscarried out in a sealed tube or sealed reaction vessel. The conversionof the bromide into alkoxy derivatives may also be carried out accordingto procedures described in Palucki, M.; Wolfe, J. P.; Buchwald, S. L.;J. Am. Chem. Soc. 1997, 119(14), 3395-3396; Yamato, T.; Komine, M.;Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303; Rychnovsky, S.D.; Hwang, K.; J. Org. Chem. 1994, 59(18), 5414-5418. Conversion of thebromide to the fluoro derivative (Step U, Scheme 2A) may be accomplishedaccording to Antipin, I. S.; Vigalok, A. I.; Konovalov, A. I.; Zh. Org.Khim. 1991, 27(7), 1577-1577; and Uchibori, Y.; Umeno, M.; Seto, H.;Qian, Z.; Yoshioka, H.; Synlett. 1992, 4, 345-346. Conversion of thebromide to the chloro derivative (Step U, Scheme 2A) may be accomplishedaccording to procedures described in Gilbert, E. J.; Van Vranken, D. L.;J. Am. Chem. Soc. 1996, 118(23), 5500-5501; Mongin, F.; Mongin, O.;Trecourt, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1996, 37(37),6695-6698; and O'Connor, K. J.; Burrows, C. J.; J. Org. Chem. 1991,56(3), 1344-1346. Steps V, W and X of Scheme 2A are carried outaccording to the procedures previously described for Steps B, C, and Dof Scheme 1, respectively. The steps of Scheme 5 may be carried out in adifferent order as shown in Scheme 6 and Scheme 7.

Scheme 8 shows the synthesis of 4-azaindole derivatives 1b-5b,5-azaindole derivatives 1c-5c, and 7-azaindole derivatives 1d-5d. Themethods used to synthesize 1b-5b, 1c-5c, and 1d-5d are the same methodsdescribed for the synthesis of 1a-5a as described in Scheme 3. It isunderstood, for the purposes of Scheme 8, that 1b is used to synthesize2b-5b, 1c provides 2c-5c and Id provides 2d-5d.

The compounds where there is a single carbonyl between the azaindole andgroup W can be prepared by the method of Kelarev, V. I.; Gasanov, S.Sh.; Karakhanov, R. A.; Polivin, Yu. N.; Kuatbekova, K. P.; Panina, M.E.; Zh. Org. Khim 1992, 28(12), 2561-2568. In this method azaindoles arereacted with trichloroacetyl chloride in pyridine and then subsequentlywith KOH in methanol to provide the 3-carbomethoxy azaindoles shown inScheme 4 which can then be hydrolyzed to the acid and carried throughthe coupling sequence with HW(C═O)A to provide the compounds of FormulaI wherein a single carbonyl links the azaindole moiety and group W.

An alternative method for carrying out the sequence outlined in stepsB-D (shown in Scheme 8) involves treating an azaindole, such as 11,obtained by procedures described in the literature or from commercialsources, with MeMgI and ZnCl₂, followed by the addition of ClCOCOCl(oxalyl chloride) in either THF or Et₂O to afford a mixture of a glyoxylchloride azaindole, 12a, and an acyl chloride azaindole, 12b. Theresulting mixture of glyoxyl chloride azaindole and acyl chlorideazaindole is then coupled with mono-benzoylated piperazine derivativesunder basic conditions to afford the products of step D as a mixture ofcompounds, 13a and 13b, where either one or two carbonyl groups link theazaindole and group W. Separation via chromatographic methods which arewell known in the art provides the pure 13a and 13b. This sequence issummarized in Scheme 10, below.

Scheme 11 depicts a general method for modifying the substituent A.Coupling of H—W—C(O)OtBu using the conditions described previously for Win Scheme 1, Step D provides Boc protected intermediate, 15.Intermediate 15 is then deprotected by treatment with an acid such asTFA, hydrochloric acid or formic acid using standard solvents oradditives such as CH₂Cl₂, dioxane, or anisole and temperatures between−78° C. and 100° C. Other acids such as aq hydrochloric or perchloricmay also be used for deprotection. Alternatively other nitrogenprotecting groups on W such as Cbz or TROC, may be utilized and could beremoved via hydrogenation or treatment with zinc respectively. A stablesilyl protecting group such as phenyl dimethylsilyl could also beemployed as a nitrogen protecting group on W and can be removed withfluoride sources such as tetrabutylammonium fluoride. Finally, the freeamine is coupled to acid A-C(O)OH using standard amine-acid couplingconditions such as those used to attach group W or as shown below foramide formation on positions R₁-R₄ to provide compound 16.

Scheme 12a preferred method for preparing HW—C(O)-A. Specific detailsare contained in the experimental section. Additional examples of thepreparation of 3-amino and 3-aminomethylpyrrolidines are described inPatane et al PCT Patent Application WO 98/57640. Scheme 13 depicts aspecific route to compounds of the invention Q in which Q is an indolewith a dicarbonyl at the 3 position and W is an aminomethyl pyrollidineattached to Q via the primary amine. A specific procedure where A isphenyl is contained in the experimental. Q could also be alternativeindoles and azaindoles and A other substituents as needed to preparecompounds of the invention. Scheme 14 describes a similar sequenceexcept that the amino methyl pyrrolidine, W is attached to thedicarbonyl via the secondary ring nitrogen and A is -OtBu. As shown,acidic removal of the tertbutoxycarbonyl group provides a free primaryamine or amine hydrochloride which may be reacted with acyl chlorides orchloroformates to give additional compounds of the invention withvarious A groups. The example where A is phenyl is described in detailin the experimental section. Scheme 15 describes similar chemistry butshows how the 7-position of the indole may be functionalized by analdehyde, carboxylic acid, or methyl carboxamide. This sequence is alsodescribed in the experimental section. A chemist skilled in the art canrecognize how this chemistry could be utilized on other examples whereQ, W, and A are modified.

As shown below in Scheme 16, step a13, suitable substituted indoles,such as the bromoindole intermediate, 10, may undergo metal mediatedcouplings with aryl groups, heterocycles, or vinyl stannanes to providecompounds within Formula I wherein R⁵ is aryl, heteroaryl, orheteroalicyclic for example. The bromoindole intermediates, 10 (orindole triflates or iodides) may undergo Stille-type coupling withheteroarylstannanes as shown in Scheme 17, step a14. Conditions for thisreaction are well known in the art and references 72-74 as well asreference 91 provide numerous conditions in addition to the specificexamples provided in Scheme 17 and in the specific embodiments. It canbe well recognized that an indole stannane could also couple to aheterocyclic or aryl halide or triflate to construct compounds ofFormula I. Suzuki coupling (reference 71) between the bromointermediate, 10, and a suitable boronate could also be employed andsome specific examples are contained in this application. Other Suzukiconditions, partners, and leaving groups have utility. Suzuki couplingsbetween chloro intermediates are also feasible. If standard conditionsfail new specialized catalysts and conditions can be employed.Procedures describing catalysts which are useful for coupling boronateswith aryl and heteroaryl chlorides are known in the art (reference 100a-g). The boronate could also be formed on the indole and then subjectedto Suzuki coupling conditions. The same coupling methodologies may beused in the case where Q contains azaindoles rather than indoles.

Chemistry

All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

LC/MS Method (i.e. Compound Identification)

Note: column A is used unless otherwise indicated in the preparation ofintermediates or examples.

-   Column A: YMC ODS-A S7 3.0×50 mm column-   Column B: PHX-LUNA C18 4.6×30 mm column-   Column C: XTERRA ms C18 4.6×30 mm column-   Column D: YMC ODS-A C18 4.6×30 mm column-   Column E: YMC ODS-A C18 4.6×33 mm column-   Column F: YMC C18 S5 4.6×50 mm column-   Column G: XTERRA C18 S7 3.0×50 mm column-   Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent    R_(t) in min.-   Gradient time: 2 minutes-   Hold time 1 minute-   Flow rate: 5 mL/min-   Detector Wavelength: 220 nm-   Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid-   Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid

Compounds purified by preparative HPLC were diluted in MeOH (1.2 mL) andpurified using the following methods on a Shimadzu LC-10A automatedpreparative HPLC system or on a Shimadzu LC-8A automated preparativeHPLC system with detector (SPD-10AV UV-VIS) wavelength and solventsystems (A and B) the same as above.

Preparative HPLC Method (i.e. Compound Purification)

Purification Method Initial gradient (40% B, 60% A) ramp to finalgradient (100% B, 0% A) over 20 minutes, hold for 3 minutes (100% B, 0%A)

-   Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid-   Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid-   Column: YMC C18 S5 20×100 mm column-   Detector Wavelength: 220 nm    Intermediate 1

Methanesulfonic acid 1-benzyl-pyrrolidin-3-ylmethyl ester

This transformation was carried out via the method in J. L. Marco et.al. reference 96. Methanesulfonyl chloride (0.10 mol, 7.8 mL) was addedslowly to a solution of racemic 1-benzyl-pyrrolidin-3-ol (0.085 mol, 15g) in 150 mL of dichloromethane which was stirring under a nitrogenatmosphere at a temperature of −20° C. The reaction was stirred for anadditional 1.5 h after addition was completed. The reaction was pouredinto a separatory funnel containing additional dichloromethane andwashed with five thirty mL portions of saturated aqueous sodiumbicarbonate. The organic layer was washed with one portion of water andthen one portion of saturated aq NaCl. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo to provide22.75 g of crude mesylate which was used directly followingcharacterization by proton NMR and LC/MS.

Intermediate 2

1-Benzyl-pyrrolidine-3-carbonitrile

This transformation was carried out using the method described in C.Thomas et. al. reference 97. The mesylate of racemic1-benzyl-pyrrolidin-3-ol (0.039 mol, 10 g), prepared as described above,sodium cyanide (0.24 mol, 15 g) and tetrabutylammonium cyanide (10 g,0.037 mol) in 75 mL of DMSO was stirred at 80-85° C. for 16 h. Thereaction mixture was partitioned between diethyl ether and sat. aqsodium bicarbonate. The aqueous layer was extracted twice with ether andthe combined organic layer was washed successively with sodiumbicarbonate, water, and sat aq. NaCl. The organic layer was dried overanhydrous magnesium sulfate, concentrated, and purified by flashchromatography over silica gel using a gradient of 20 to 30% ethylacetate in hexane to afford 5.5 g of the desired product.

Intermediate 3

C-(1-Benzyl-pyrrolidin-3-yl)-methylamine

This reaction was carried out according to the procedure in M. R. Paviaet. al. reference 98. The nitrile (0.03 mol, 5.5 g) was dissolved in THFand cooled to 0° C. Lithium aluminum hydride (0.03 mol, 1.14 g) wasadded into the solution in one portion. After the addition was finished,the cooling bath was removed and the reaction was stirred at ambienttemperature for 18 h. The reaction was filtered and the filtrate was aconcentrated in vacuo to provide the crude product which was useddirectly in the next reaction.

Intermediate 4

(1-Benzyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester

A mixture of crude amine (0.028 mol, 5.3 g), triethylamine (0.034 mol,4.7 mL), and ditertbutyl dicarbonate (0.034 mol, 7.4 g) indichloromethane was stirred at ambient temperature for 3 h. The reactionwas diluted with dichloromethane, and then washed with water and thensat aq NaCl. The organic extract was dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Purification via flashchromatography over silica gel provided 4.2 g of the desired carbamate.1H NMR (300 MHz, CDCl3): 7.32˜7.30(m, 5H), 3.59˜3.58(m, 2H),3.17˜3.02(m, 2H), 2.73˜2.28(m, 5H), 2.04˜1.90(m, 1H), 1.60˜1.48(m, 1H),1.45(s,9H).

Intermediate 5

Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester

The benzyl amine (4.2 g) and 2.1 g of 10% Pd/C in methanol was shakenunder 50 PSI of hydrogen on a Parr apparatus for 20 h. The reactionmixture was filtered through celite and concentrated in vacuo to give aresidue which was used directly without further purification. 1H NMR(300 MHz, CDCl3): 3.15˜1.82(m, 8H), 1.55˜1.45(m, 1H), 1.43(s,9H).

Intermediate 6

(1-Benzoyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester

The amine (14.65 mmol, 2.93 g) was dissolved in dichloromethane andtreated with DMAP (14.65 mmol, 1.79 g), EDC (14.65 mmol, 2.80 g), andthen benzoic acid (13.18 mmol, 0.9 eq). The reaction was stirred for 16h at ambient temperature and then diluted with dichloromethane. Theorganic layer was washed with water and sat aq. NaCl and dried overanhydrous sodium sulfate. The solution was filtered and concentrated invacuo to provide a residue which was purified by flash chromatographyover silica gel to provide 3.06 g of the desired benzamide. 1H NMR (300MHz, CDCl3): 7.55˜7.34(m, 5H), 3.80˜3.10(m, 6H), 2.55˜1.58(m, 3H),1.40(s,9H).

Intermediate 7

(3-Aminomethyl-pyrrolidin-1-yl)-phenyl-methanone

The carbamate was stirred in 20 mL of 4N HCl in dioxane for 20 h. Thereaction mixture was concentrated on a rotary evaporator and dried undervacuum to provide the hydrochloride salt which was used directly withoutfurther purification.

EXAMPLE 1N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-1H-indol-3-yl)-2-oxo-acetamide

The acid chloride (1 mmol, 225 mg) was added to a solution of the aminehydrochloride (1 mmol, 240 mg) and diisopropyl ethyl amine (10 mmol,1.74 mL) in 5 mL of anhydrous THF under a nitrogen atmosphere. Thereaction was stirred for 16 h at ambient temperature and then pouredinto ethyl acetate. The organic layer was washed with water and then sataq NaCl and then dried over anhydrous magnesium sulfate. Filtration andconcentration in vacuo provided a crude product which was purified byflash chromatography over silica gel to provide 208 mg of the desiredN-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-1H-indol-3-yl)-2-oxo-acetamide.

1H NMR (500 MHz, CD3OD): 8.69 (s), 8.56 (s), 1H. 7.55˜7.40 (m, 5H),7.31˜7.20 (m, 2H), 6.96˜6.87 (m, 1H), 3.81˜3.29 (m, 6H), 2.70˜1.73 (m,3H).

LC/MS: (ES+) m/z (M+H)+=394, RT=1.06.

EXAMPLE 2{1-[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-carbamicacid tert-butyl ester

The acid chloride (2 mmol, 453 mg) was added to a solution of the aminehydrochloride (2 mmol, 400 mg) and diisopropyl ethyl amine (4 mmol, 0.7mL) in 12 mL of anhydrous THF under a nitrogen atmosphere. The reactionwas stirred for 18 h at ambient temperature and then poured into ethylacetate. The organic layer was washed with water and then sat aq NaCland then dried over anhydrous magnesium sulfate. Filtration andconcentration in vacuo provided a crude product which was purified byflash chromatography over silica gel to provide 475 mg of the desired3-{[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetylamino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester.

1H NMR (500 MHz, CD3OD): 8.17(s), 8.14(S), 1H. 7.32˜7.24(m, 2H),6.97˜6.93(m, 1H), 3.73˜3.04(m, 6H), 2.46˜2.43(m, 1H), 2.09˜2.01(m, 1H),1.74˜1.73(m, 1H), 1.44(s, 9H).

Intermediate 8

The carbamate was stirred in 15 mL of 4N HCl in dioxane for 20 h. Thereaction mixture was concentrated on a rotary evaporator and dried undervacuum to provide the hydrochloride salt which was used directly withoutfurther purification.

EXAMPLE 3N-{1-[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benzamideand Example 4N-{1-[2-(1-Benzoyl-4-fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benzamide

Benzoyl chloride (0.46 mmol, 54 μL) and then diisopropyl ethyl amine(0.92 mmol, 0.16 mL) were added to a stirring solution of aminehydrochloride (0.46 mmol, 150 mg) in 5 mL of THF under an atmosphere ofnitrogen at ambient temperature. The reaction was stirred for 18 h andthen the THF was removed in vacuo. The residue was dissolved in ethylacetate and washed with water and then sat aq NaCl. The organic extractwas dried, filtered, concentrated, and purified via flash chromatographyto the desired product of example 3:

1H NMR (500 MHz, CD3OD): 8.18 (s), 8.14 (s), 1H. 7.85˜7.82 (m, 1H),7.72˜7.68 (m, 1H), 7.54˜7.24 (m, 5H), 6.97˜6.90 (m, 1H), 3.80˜3.29 (m,6H), 2.67˜2.61 (m, 1H), 2.20˜2.05(m, 1H), 1.87˜1.81(m, 1H).

LC/MS: (ES+) m/z (M+H)+=394, RT=1.74.

and the bis benzylated product Example 4 which resulted from a secondbenzylation of the indole nitrogen:

LC/MS: (ES+) m/z (m+H)+=498; RT=1.46

EXAMPLE 5N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-7-formyl-1H-indol-3-yl)-2-oxo-acetamide

DEPBT (2.13 mmol, 514 mg) was added to a stirring solution of thealdehyde acid (prepared as described in WO 00/76521, 2.13 mmol, 500 mg),amine hydrochloride (2.13 mmol, 514 mg), and diisopropyl ethylamine(4.26 mmol, 0.74 mL) in 5 mL of DMF at ambient temperature. The reactionwas stirred for 16 h and then the DMF was removed in vacuo. The residuewas dissolved in ethyl acetate and water was added. After separation thewater layer was reextracted with ethyl acetate. The combined organicextracts were dried over anhydrous magnesium sulfate, concentrated andchromatographed over silica gel to provide the desired product.

1H NMR (300 MHz, CD3OD): 10.06 (s, 1H); 8.79 (s), 8.72 (s), 1H,7.89˜7.84 (m, 1H); 7.53˜7.40 (m, 5H); 7.15˜7.06 (m, 1H); 3.81˜3.29 (m,6H); 2.68˜2.51 (m, 1H); 2.17˜2.00 (m, 1H); 1.87˜1.72 (m, 1H).

LC/MS: (ES+) m/z (m+H)+=422; RT=1.29.

EXAMPLE 6N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-oxo-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-acetamide

DEPBT (1.32 mmol, 395 mg) was added to a stirring solution of thepotassium salt (prepared as described in WO 01/62255, 1.32 mmol, 300mg), amine hydrochloride (1.32 mmol, 318 mg), and diisopropyl ethylamine(2.64 mmol, 0.46 mL) in 3 mL of DMF at ambient temperature. The reactionwas stirred for 16 h and then the DMF was removed in vacuo. The residuewas dissolved in ethyl acetate and water was added. After separation thewater layer was reextracted with ethyl acetate. The combined organicextracts were washed with sat aq NaCl, dried over anhydrous magnesiumsulfate, concentrated and chromatographed over silica gel to provide 268mg of the desired product.

1H NMR (500 MHz, CD3OD): 8.92˜8.89 (m), 8.81˜8.79 (m), 1H, 8.68˜8.60 (m,1H); 8.34˜8.8.32 (m, 1H); 7.54˜7.43 (m, 5H); 7.33˜7.7.26 (m, 1H);3.96˜3.26 (m, 6H); 2.66˜2.52 (m, 1H); 2.16˜2.05 (m, 1H); 1.85˜1.74 (m,1H).

LC/MS: (ES+) m/z (m+H)+=377; RT=1.18

EXAMPLE 73-(1-Benzoyl-pyrrolidin-3-ylmethyl)-aminooxalyl)-4-fluoro-1H-indole-7-carboxylicacid

Silver nitrate (AgNO3, 1.48 mmol, 252 mg) was dissolved in 2 mL ofwater. A solution of NaOH (2.96 mmol, 118 mg) in 2 mL of methanol and 2mL of water was added to the silver nitrate solution and a brownprecipitate formed. The aldehyde

(0.74 mmol, 313 mg) was added into the solution/precipitate in oneportion. The reaction was heated to 90° C. and stirred for 15 h. Aftercooling to ambient temperature, the reaction was filtered through celiteusing ethyl acetate washes. The filtrate was extracted with ethylacetate. The aqueous layer was acidified with 2N HCl to about PH 2. Theresulting solid was collected by filtration to give the desired acid. 1HNMR (500 MHz, CD3OD): 8.79 (s), 8.70 (s), 1H; 8.05˜7.92 (m, 1H);7.53˜7.44 (m, 5H); 7.05˜6.93 (m, 1H); 3.78˜3.26 (m, 6H); 2.66˜2.53 (m,1H); 2.17˜2.06 (m, 1H); 1.84˜1.75 (m, 1H).

LC/MS: (ES+) m/z (m+H)+=438; RT=1.33.

EXAMPLE 83-(1-Benzoyl-pyrrolidin-3-ylmethyl)-aminooxalyl)-4-fluoro-1H-indole-7-carboxylicacid methylamide

The acid (19 mg, 1 equivalent) was dissolved in 1 mL of DMF and 1.5equivalents of 1,1-carbonyl diimidazole was added. The reaction wasstirred at ambient temperature for 15 mm and then 4 equivalents (0.1 ml)of 2N methyl amine in THF was added. The reaction was stirred overnightand then the DMF was removed in vacuo. The residue was chromatographedto afford 12 mg of the desired methyl amide.

LC/MS: (ES+) m/z (m+H)+=451; RT=1.26

EXAMPLE 9N-{1-[2-(7-Bromo-4-fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benzamide

The ketoacid (0.97 mmol, 280 mg), the amine (0.97 mmol, 200 mg) anddiisopropyl ethyl amine (0.34 mL) and DEPBT (0.97 mmol, 292 mg) weredissolved in 2 mL of dry DMF under an atmosphere of nitrogen. Thereaction was stirred for 36 h at ambient temperature and then pouredinto 10 mL of ethyl acetate. The organic layer was washed with two 10 mLportions of water and then the aqueous layer was back extracted with 10mL of EtOAc. The combined organic extracts were dried over anhydrousmagnesium sulfate. Filtration and concentration in vacuo provided acrude product which was purified by flash chromatography over silica gelusing gradients of 50 to 100% EtOAc:Hexane then 2 to 5% MeOH/EtOAc toprovide 29 mg of the desired amide as a light brown solid.

1H NMR (500 MHz, CD3OD): 8.43 (s), 8.38 (s), 1H, 8.01˜7.97 (m, 1H);7.83˜7.79 (m, 1H); 7.69˜7.34 (m, 4H); 4.13˜1.20 (m, 9H).

LC/MS: (ES+) m/z (m+H)+=475; RT=1.27.

EXAMPLE 10N-{1-[2-(7-Bromo-4-fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benzamide

The ketoacid (0.97 mmol, 280 mg), the amine (0.97 mmol, 200 mg) anddiisopropyl ethyl amine (0.34 mL) and DEPBT (0.97 mmol, 292 mg) weredissolved in 2 mL of dry DMF under an atmosphere of nitrogen. Thereaction was stirred for 36 h at ambient temperature and then pouredinto 10 mL of ethyl acetate. The organic layer was washed with two 10 mLportions of water and then the aqueous layer was back extracted with 10mL of EtOAc. The combined organic extracts were dried over anhydrousmagnesium sulfate. Filtration and concentration in vacuo provided acrude product which was purified by flash chromatography over silica gelusing gradients of 50 to 100% EtOAc:Hexane then 2 to 5% MeOH/EtOAc toprovide 108 mg of the desired amide as a yellow solid.

1H NMR (500 MHz, CD3OD): 8.43 (s), 8.39 (s), 1H, 8.02˜7.97 (m, 1H);7.84˜7.81 (m, 1H); 7.69˜7.66 (m, 1H); 7.54˜7.35 (m, 3H); 4.13˜1.21 (m,9H)

LC/MS: (ES+) m/z (m+H)+=475; RT=1.19, 1.27.

EXAMPLE 11N-(1-{2-[4-Fluoro-7-(1H-pyrazol-3-yl)-1H-indol-3-yl]-2-oxo-acetyl}-pyrrolidin-3-ylmethyl)-benzAmide

The bromide (0.12 mmol, 59 mg), the pyrazole stannane (0.24 mmol, 86mg), and palladium tetrakis triphenyl phosphine (0.012 mmol, 14 mg) weredissolved in 0.5 mL of dry dioxane and heated in a sealed tube at 140 to145° C. for 17 h. After cooling to room temperature, the reaction wasfiltered through filter paper and the filtrate concentrated by rotaryevaporation. The residue was dissolved in 2 mL of MeOH and purifiedusing preparative thin layer chromatography to provide 12.6 mg of thedesired pyrazole as a light yellow solid.

1H NMR (500 MHz, CD3OD): 8.62˜8.57 (m, 1H), 8.32˜8.30 (m, 1H); 7.92˜7.15(m, 10H); 4.05˜1.82 (m, 9H)

LC/MS: (ES+) m/z (m+H)+=475; RT=1.01, 1.10.

EXAMPLE 12N-(1-{2-[4-Fluoro-7-(1H-pyrazol-3-yl)-1H-indol-3-yl]-2-oxo-acetyl}-pyrrolidin-3-ylmethyl)-benzamide

The bromide (0.046 mmol, 22 mg), the pyrazole stannane (0.092 mmol, 33mg), and palladium tetrakis triphenyl phosphine (10 mg) were dissolvedin 0.5 mL of dry dioxane and heated in a sealed tube at 140 to 145° C.for 17 h. After cooling to room temperature, the reaction was filteredthrough filter paper and the filtrate concentrated by rotaryevaporation. The residue was dissolved in 2 mL of MeOH and purifiedusing preparative thin layer chromatography to provide 4.8 mg of thedesired pyrazole as a light yellow solid.

1H NMR (500 MHz, CD3OD): 8.60˜8.54 (m, 1H), 8.29˜8.28 (m, 1H); 7.91˜7.15(m, 10H); 4.06˜1.80 (m, 9H)

LC/MS: (ES+) m/z (m+H)+=475; RT=1.01, 1.10.

EXAMPLE 132-(N-benzoylaminoethyl)-1-[(indol-3-yl)-2-oxoacetyl]-pyrrolidine

Preparation of compound C,2-(N-benzoylaminoethyl)-1-[(indol-3-yl)-2-oxoacetyl]-pyrrolidine

Tri-ethylamine (1 ml) was added into a solution of indole-3-glyoxyloylchloride, intermediate 9 (50 mg, purchased from Lancaster) andintermediate 10 2-(N-benzoylaminoethyl)-pyrrolidine (49 mg, Wang, et al,Tetrahedron Lett. 1999, 40, 6745-6747) in THF (5 ml). After the reactionwas stirred for 10 hours, the solvents were removed under vacuum toafford a residue which was purified using Shimadzu automated preparativeHPLC System to give2-(N-benzoylaminoethyl)-1-[(indol-3-yl)-2-oxoacetyl]-pyrrolidine (20mg). Start %=0

-   Final %=100-   Gradient time=2 minute-   Flow Rate=5 ml/min-   Wavelength=220-   Column: XTERRA ms C18 4.6×30 mm-   Rf=1.57 minute-   MS (M+H) for C22H22N3O3-   Cald=376.17-   Obsd=376.23

EXAMPLE 14 1H-Indole-3-carboxylic acid(1-benzoyl-pyrrolidin-3-yl)-methyl-amide

The procedure is the same as the following one, which was described inBlair et. al. PCT WO 00/76521

Indole 3-carboxylic acid, (2.0 g) was dissolved in 5 ml of SOCl₂. Themixture was heated to reflux for 30 minutes. Removal of excess of SOCl₂under vacuum provided intermediate 9, indole 3-carbonyl chloride, whichwas carried to the next step without further purification.

A mixture of indole 3-carbonyl chloride, intermediate 9 (50 mg),N-Benzoyl-3-methylamino-pyrrolidine, intermediate 10, (57 mg), pyridine(44 mg) in THF (5 ml) was stirred at room temperature for 10 hours.Solvents were removed under vacuum, and the residue was purified using aShimadzu automated preparative HPLC System to give 78 mg of the compoundof example 14,N-Benzoyl-3-[N-(indol-3-yl-carbonyl)-N-methyl]amino-pyrrolidine:

MS m/z: (M+H)⁺ calcd for C₂₁H₁₉FN₃O₃: 348.17. found 348.22. HPLCretention time: 1.40 p minutes (column A).

Biology

-   -   “μM” means micromolar;    -   “mL” means milliliter;    -   “μl” means microliter;    -   “mg” means milligram;

The materials and experimental procedures used to obtain the resultsreported in Tables 1-2 are described below.

Cells:

-   -   Virus production—Human embryonic Kidney cell line, 293,        propagated in Dulbecco's Modified Eagle Medium (Life        Technologies, Gaithersburg, Md.) containing 10% fetal Bovine        serum (FBS, Sigma, St. Louis, Mo.).    -   Virus infection—Human epithelial cell line, HeLa, expressing the        HIV-1 receptors CD4 and CCR5 was propagated in Dulbecco's        Modified Eagle Medium (Life Technologies, Gaithersburg, Md.)        containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.)        and supplemented with 0.2 mg/mL Geneticin (Life Technologies,        Gaithersburg, Md.) and 0.4 mg/mL Zeocin (Invitrogen, Carlsbad,        Calif.).        Virus—Single-round infectious reporter virus was produced by        co-transfecting human embryonic Kidney 293 cells with an HIV-1        envelope DNA expression vector and a proviral cDNA containing an        envelope deletion mutation and the luciferase reporter gene        inserted in place of HIV-1 nef sequences (Chen et al, Ref. 41).        Transfections were performed using lipofectAMINE PLUS reagent as        described by the manufacturer (Life Technologies, Gaithersburg,        Md.).        Experiment

-   1. Compound was added to HeLa CD4 CCR5 cells plated in 96 well    plates at a cell density of 1×10³ cells per well in 100 μl    Dulbecco's Modified Eagle Medium containing 10% fetal Bovine serum    at a concentration of <20 μM.

-   2. 100 μl of single-round infectious reporter virus in Dulbecco's    Modified Eagle Medium was then added to the plated cells and    compound at an approximate multiplicity of infection (MOI) of 0.01,    resulting in a final volume of 200 μl per well and a final compound    concentration of <10 μM.

-   3. Samples were harvested 72 h after infection.

-   4. Viral infection was monitored by measuring luciferase expression    from viral DNA in the infected cells using a luciferase reporter    gene assay kit (Roche Molecular Biochemicals, Indianapolis, Ind.).    Infected cell supernatants were removed and 50 μl of Dulbecco's    Modified Eagle Medium (without phenol red) and 50 μl of luciferase    assay reagent reconstituted as described by the manufacturer (Roche    Molecular Biochemicals, Indianapolis, Ind.) was added per well.    Luciferase activity was then quantified by measuring luminescence    using a Wallac microbeta scintillation counter.

-   5. The percent inhibition for each compound was calculated by    quantifying the level of luciferase expression in cells infected in    the presence of each compound as a percentage of that observed for    cells infected in the absence of compound and subtracting such a    determined value from 100.

-   6. An EC₅₀ provides a method for comparing the antiviral potency of    the compounds of this invention. The effective concentration for    fifty percent inhibition (EC₅₀) was calculated with the Microsoft    Excel Xlfit curve fitting software. For each compound, curves were    generated from percent inhibition calculated at 10 different    concentrations by using a four parameter logistic model (model 205).    The EC₅₀ data for the compounds is shown in Tables 2-4. Table 1 is    the key for the data in Table 2.    Results

TABLE 1 Biological Data Key for EC₅₀s Compounds with Compounds*Compounds EC50 >50 nM but with EC₅₀s with EC₅₀s >1 not yet tested atCompounds with >5 μM μM but <5 μM higher concentrations EC50 <1 μM GroupC Group B Group A′ Group A *Some of these compounds may have been testedat a concentration lower than their EC₅₀ but showed some ability tocause inhibition and thus should be evaluated at a higher concentrationto determine the exact EC₅₀.In Tables 2-5, X₂, X₄ etc. indicates the point of attachment.

TABLE 2

Examples EC₅₀ Table Entry Group (Example from Number.) Z W A Table 11(Example 1)

A 2(Example 2)

C 3(Example 3)

A 4(Example 4)

A 5(Example 5)

B 6(Example 6)

C 7(Example 7)

B 8(Example 8)

A 9(Example 9)

A 10(Example10)

A 11(Example11)

A 12(Example12)

A 13(Example13)

A 14(Example14)

C 15(Example15)

C 16(Example16)

A′

The compounds of the present invention may be administered orally,parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand diluents.

Thus, in accordance with the present invention, there is furtherprovided a method of treating and a pharmaceutical composition fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition comprising a pharmaceutical carrier and atherapeutically effective amount of a compound of the present invention.

The pharmaceutical composition may be in the form of orallyadministrable suspensions or tablets; nasal sprays, sterile injectablepreparations, for example, as sterile injectable aqueous or oleagenoussuspensions or suppositories.

When administered orally as a suspension, these compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents, and lubricants known in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this invention can be administered orally to humans ina dosage range of 1 to 100 mg/kg body weight in divided doses. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weight individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

1. A compound of Formula I, including pharmaceutically acceptable saltsthereof

wherein: Z is

A is selected from the group consisting of phenyl and D; wherein D isselected from the group consisting of pyridinyl, furanyl and thienyl;wherein phenyl and D are independently optionally substituted with oneor two of the same or different amino or halogen; W is selected from thegroup consisting of

R¹ is hydrogen; and Q is a member selected from the groups (A) and (B)consisting of

provided R² and R³ are each independently hydrogen, methoxy or halogen;and R⁴ and R⁵ are selected from the group consisting of hydrogen,halogen, cyano, COOR⁸, C(O)NHCH₃, C(O)NHheteroaryl, and heteroaryl; and

provided R² is hydrogen, methoxy or halogen; R³ and R⁴ are selected fromthe group consisting of hydrogen, halogen, methoxy, cyano, COOR⁸,C(O)NHCH₃, C(O)NHheteroaryl and heteroaryl; and R⁶ does not exist;and - - represents a carbon-carbon bond in (A) and (B); R⁷ is(CH₂)_(n)R⁴⁴ wherein n is 0-6; R⁸ is selected from the group consistingof hydrogen and (C₁₋₆)alkyl; R⁹ is selected from the group consisting ofhydrogen and methyl; R⁴⁴ is selected from the group consisting of H,(C₁₋₆)alkyl, CO(C₁₋₆)alkyl, C(O)— phenyl and —CONR_(a)R_(b); R_(a) andR_(b) are each independently H, (C₁₋₆)alkyl or phenyl.
 2. Apharmaceutical composition which comprises an antiviral effective amountof a compound of Formula I, including pharmaceutically acceptable saltsthereof, as claimed claim 1, and one or more pharmaceutically acceptablecarriers, excipients or diluents.